tbuckley/cabot-search huggingface dataset:
The Medicare Appropriate Use Criteria Program: A Review of Recommendations for Testing in Coronary Artery Disease
Authors: David E. Winchester, Friederike K. Keating, Krishna K. Patel, Nishant R. Shah
Journal: Annals of Internal Medicine (2023)

Background: Congress established the Appropriate Use Criteria (AUC) Program to reduce unnecessary advanced imaging studies. Organizations that wish to develop AUC can apply to the Centers for Medicare & Medicaid Services (CMS) to qualify as provider-led entities (PLEs) under this program. Variable methods, content, and formatting of PLE-generated AUC could lead to clinician uncertainty about whether an advanced imaging test is appropriate or not. Purpose: To review AUC published by CMS-qualified PLEs focused on advanced imaging tests for coronary artery disease (CAD), a “priority clinical area” identified by CMS. Data Sources: Publicly available data from the worldwide web searched on 29 August 2022. Study Selection: Approved AUC with recommendations related to testing for CAD. Data Extraction: Manual review of published AUC by all authors. Data Synthesis: Among the 17 CMS-qualified PLEs, only 7 had published AUC related to CAD. Substantial variation in the methods and formatting of these AUCs was observed. The number of clinical scenarios covered ranged from 6 to 210, and the number of advanced imaging methods covered ranged from 1 to 25. When specifically applied to clinical scenarios, many AUC offered no guidance on appropriateness; those that did conflicted with respect to appropriateness. Limitation: Other CMS-identified priority clinical areas were not evaluated. Conclusion: CMS-qualified AUC for imaging of CAD are heterogeneous and sometimes discrepant, creating substantial potential for uncertainty among clinicians seeking to provide their patients with appropriate imaging tests. Primary Funding Source: No funding was received for this study.
The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence
Authors: Liam Bendicksen, Diana M. Zuckerman, Jerry Avorn, Sophia Phillips, Aaron S. Kesselheim
Journal: Annals of Internal Medicine (2023)

The U.S. Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for Duchenne muscular dystrophy in 2016 via its accelerated approval program on the basis of a study of 12 boys. After a contentious review process and a high-profile meeting of an external advisory committee, FDA leaders concluded that very small increases in treated patients' levels of dystrophin, a muscle protein, were reasonably likely to predict clinical benefit. The eteplirsen approval, which was followed by approvals of other drugs in the same class via the same pathway, has been controversial because of the questionable evidence underlying these decisions, delays in mandated postapproval testing, and high U.S. prices. Questions remain about the effectiveness and long-term safety of these products. Although the FDA initially set a November 2020 deadline for eteplirsen's manufacturer to complete a clinical trial determining whether the drug has clinical benefit, the company will not complete the trial until 2024 or later. The relationship between levels of truncated dystrophin, the muscle protein studied in eteplirsen's pivotal trial, and clinical outcomes remains uncertain. Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.
P366: ARE MINIMAL RESIDUAL DISEASE MEASUREMENTS AFTER CONSOLIDATION THERAPY USEFUL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA?
Authors: Janine Stutterheim, Rachella Van der Waarden, Hester de Groot-Kruseman, Edwin Sonneveld, Valerie De Haas, Ellen C Van der Schoot, Vincent van der Velden, Rana Dandis, Rob Pieters
Journal: HemaSphere (2023)

Background: Bone marrow examinations are often performed after consolidation in patients with negative or low MRD levels end of first consolidation (EOC). The question remains whether these measurements are useful for detecting (molecular) relapse and predicting outcome. We investigated the prognostic significance and clinical relevance of MRD measurements after EOC in medium risk patients with low MRD levels (< 0.05%) at EOC. Aims: We sought for answers for the two following questions: What is the prognostic value of MRD at later time points if 1) EOC MRD is negative and if 2) EOC MRD is positive. Methods: MRD measurements were analyzed in 271 medium risk (MR) children with ALL treated in DCOG ALL-10. MRD results were available at EOC (Time point (TP)2; n= 269), at end of consolidation II/start of intensification(TP3; n= 252), week 19 maintenance (TP4; n=251), and week 37 maintenance (TP5; n= 263). Results were validated in a cohort of patients treated in DCOG ALL-9 (n=121). MRD was measured by PCR analysis of immunoglobulin and/or T-cell receptor genes. Relapse free survival (RFS) was used as endpoint. Results: Patients being MRD negative EOC (n=178) had excellent outcome, irrespective of the MRD results at later time points; 6-years RFS of 92.6% (SE 2.1) for those with MRD negativity at all later time points compared to 96.2% (3.8) for those with one or more later time points being positive (p=0.46). Patients with positive EOC MRD (n=91) of whom the subsequent time points were MRD negative (n=43) had a comparable good outcome, with a 6-y RFS of 93.0% (SE 3.9). Patients being MRD positive at EOC and MRD positivity at one or more subsequent time points (n=48) had a higher risk of relapse, 6y RFS 69.1% (SE 6.6), p =0.002. These findings were confirmed in the validation cohort of ALL-9 patients. Summary/Conclusion: We conclude that in patients with medium risk ALL, MRD measurements after the first consolidation can be abandoned in case of MRD negativity at EOC. For patients who are EOC MRD positive the subsequent MRD measurement might be informative for further risk stratification. Fig 1. Prognostic significance of EOC MRD in combination with later time points (ALL-10)Keywords: Acute lymphoblastic leukemia, MRD, Childhood
S287: HEMOGLOBIN AND FERRITIN LEVELS ADJUST DIFFERENTLY TO MODERATE AND HIGH ALTITUDE IN DIFFERENT WORLD REGIONS: EVIDENCE FOR A VERY PRECISE OXYGEN SENSING SYSTEM
Authors: Max Gassmann, Martina Muckenthaler, Heimo Mairbäurl
Journal: HemaSphere (2023)

Background: About 7% of the world’s population lives more than 1500 meters above sea level (masl) and as a consequence, the hemoglobin (Hb) levels increase. We analyzed this increased in various regions of the globe. Aims: To define the Hb levels in different populations living at different altitudes in the world regions and compare these data with the altitude adjustment suggested by the WHO. Methods: We analyzed data from the Demographic and Health Survey (DHS) Program obtained in 32 countries harboring > 4% of residents at altitudes above 1000 m. We calculated [Hb]-increase and ΔHb/km altitude. To assess whether moderate altitude is sufficient to alter Hb levels, we evaluated Hb, ferritin, and C-reactive protein (CRP) levels in relation to the residential altitude of 71,798 Swiss men aged 18-22 years joining. Results: We found the most pronounced Δ[Hb]/km in East Africans and South Americans, while [Hb] increased least in South/South-East Asia. Interestingly, in all world regions, the Δ[Hb]/km was lower in children than in adults. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. Average Hb values in Swiss man increased by a maximum of 2.84% from conscripts living between <300 and >1800 masl. Surprisingly, plasma ferritin levels significantly increased with altitude independently of the Hb, demonstrating for the first time that iron stores are subject to control by moderate altitude increases. Thus, also moderate altitude must be considered when interpreting Hb and iron levels for a given population even when residing at altitudes below 1500 masl. Summary/Conclusion: The adjustment of Hb levels at moderate altitude suggests a high precision oxygen-sensing mechanism, that most probably also functions for increasing iron stores in response to elevated altitude. The question arises as why evolution has come up with such a precise oxygen sensing system. We speculate that oxygen sensing was not initially developed to increase Hb levels but rather to protect other organs, especially the neuronal system, from reduced oxygen supply. As such, it might well be that oxygen-dependent erythropoietin expression was originally developed to exert a neuroprotective function that is still found in mammals today. Keywords: Hemoglobin, Iron
S303: A PHASE 3 STUDY (ATLAS-PPX) TO EVALUATE EFFICACY AND SAFETY OF FITUSIRAN IN PEOPLE WITH HAEMOPHILIA A OR B WHO HAVE SWITCHED FROM PRIOR CLOTTING FACTOR CONCENTRATE OR BYPASSING AGENT PROPHYLAXIS
Authors: Gili Kenet, Beatrice Nolan, Bulent Zulfikar, Bulent Antmen, Peter Kampmann, Tadashi Matsushita, Chur-Woo You, Kateryna Vilchevska, Catherine N. Bag, Azizan Sharif, Flora Peyvandi, Guy Young, Claude Negrier, Christian Sussebach, Fadi Shammas, Shauna Andersson, Baisong Mei, Kaan Kavakli
Journal: HemaSphere (2023)

Background: Fitusiran, a subcutaneous (SC) investigational siRNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or B (PwHA/B), irrespective of inhibitor status. In previous Phase 3 trials, once-monthly fitusiran prophylaxis significantly reduced annualised bleeding rate (ABR) in PwHA/B, with or without inhibitors versus episodic/on-demand treatment. Aims: To evaluate the efficacy and safety of fitusiran versus prior clotting factor concentrate (CFC)/bypassing agent (BPA) prophylaxis in PwHA/B, with or without inhibitors. Methods: This Phase 3, multinational, open-label study (NCT03549871) included males aged ≥12 years with hemophilia A or B, with or without inhibitors, who had prior CFC/BPA prophylaxis. Participants continued CFC/BPA prophylaxis (6 months) before switching to once-monthly 80 mg SC fitusiran prophylaxis (7 months). Primary endpoint was ABR in the CFC/BPA prophylaxis period (Day 168 to Day 1) and fitusiran efficacy period (Day 29 to Day 190). Secondary endpoints included spontaneous ABR (AsBR), joint ABR (AjBR), and health-related quality of life (HRQoL). Safety and tolerability were assessed. Results: Of 80 enrolled participants, 65 (inhibitor/non-inhibitor, n=19/46; haemophilia A/haemophilia B, n=50/15) were eligible for ABR analyses. Median observed (IQR) ABRs were 4.4 (2.2; 10.9) with CFC/BPA and 0.0 (0.0; 2.3) with fitusiran prophylaxis; 41 participants (63.1%) experienced zero treated bleeds with fitusiran. Fitusiran achieved statistically significant reductions in estimated ABR, AsBR and AjBR versus CFC/BPA prophylaxis (Table 1). Fitusiran significantly improved HRQoL versus CFC/BPA as measured by Haem-A-QOL total score (LS mean difference -4.6 [95% CI: -7.6; -1.5; p<0.01]). Serious adverse events (SAEs) occurred in 5/65 participants (7.7%) with CFC/BPA and 9/67 (13.4%) with fitusiran prophylaxis. A total of 17 (25.4%) participants experienced alanine aminotransferase or aspartate transaminase elevations >3x the upper limit of normal in the fitusiran prophylaxis period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Summary/Conclusion: Once-monthly fitusiran prophylaxis significantly reduced bleeding versus CFC/BPA prophylaxis with a median ABR of zero in PwHA/B with and without inhibitors, resulting in a meaningful improvement in HRQoL. Reported AEs were generally consistent with previously identified risks of fitusiran.Keywords: Hemophilia
Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients
Authors: Malte B Monin, Leona I Baier, Jens G Gorny, Moritz Berger, Taotao Zhou, Robert Mahn, Farsaneh Sadeghlar, Christian Möhring, Christoph Boesecke, Kathrin van Bremen, Jürgen K Rockstroh, Christian P Strassburg, Anna-Maria Eis-Hübinger, Matthias Schmid, Maria A Gonzalez-Carmona
Journal: Liver Cancer (2023)

Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment.In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented.In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed.Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.
Annals Graphic Medicine - Death and Dying
Authors: Colleen Alexander
Journal: Annals of Internal Medicine (2023)

Web ExclusivesSeptember 2023Annals Graphic Medicine - Death and DyingFREEColleen Alexander, MD, MS, RDColleen Alexander, MD, MS, RDEmory University, Atlanta, Georgia (C.A.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0056 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Julianne ChildsHope Community Cancer Center a division of RCCA21 August 2023 I am sorry for your loss I am so sorry for your loss. I too lost my mother suddenly. I was still in my thirties at the time working as a HEMONC and pregnant with her grandson: she never learned this. There is something so unfinished, incomplete, unsteadying losing a loved one without getting to say goodbye…I agree, suffering exists with sudden or drawn out deaths. I loved the way you told your story, through cartoon, it juxtaposed the seriousness and inane that coexisted, especially the crazy concept of being graded on the topic of “Death and Dying” while clearly an unwilling expert. I am sure your experience has made you a more empathetic physician. Take care. Marianne Parshley MD FACPProvidence Medical Group23 August 2023 Thank you Dr. Alexander, Thank you! I have been in a similar seat at that table. We need to remember all people have different life styles experiences and acknowledge emotions that arise with topics that touch our hearts. We need to teach how to recognize and accept these emotions as a normal part of humanity. We should teach how to recognize and acknowledge them and support the human need to express them (as did the quiet one) Not just move on to get done expeditiously. First step, see the person in front of us as and where they are. They are more important than schedules and what can be learned is far deeper and more important than mere facts. With gratitude, Marianne Author, Article, and Disclosure InformationAuthors: Colleen Alexander, MD, MS, RDAffiliations: Emory University, Atlanta, Georgia (C.A.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0056.Author/Illustrator Information: Colleen Alexander, MD, MS, RD, is a registered dietitian and resident physician in pathology (e-mail, colleen.alexander@emory.edu).This article was published at Annals.org on 22 August 2023. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Current IssueSeptember 2023Volume 176, Issue 9 ePublished: 22 August 2023 Issue Published: September 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Lessons From the COVID-19 Pandemic: Updating Our Approach to Masking in Health Care Facilities
Authors: Eric J. Chow, John B. Lynch, Danielle M. Zerr, Francis X. Riedo, Mary Fairchok, Steven A. Pergam, Christopher S. Baliga, John Pauk, James Lewis, Jeffrey S. Duchin
Journal: Annals of Internal Medicine (2023)
Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05)
Authors: Ernest Nadal, Delvys Rodríguez-Abreu, Marta Simó, Bartomeu Massutí, Oscar Juan, Gerardo Huidobro, Rafael López, Javier De Castro, Anna Estival, Joaquín Mosquera, Ivana Sullivan, Enriqueta Felip, Ana Blasco, Maria Guirado, Eva Pereira, Noelia Vilariño, Valentín Navarro, Jordi Bruna
Journal: Journal of Clinical Oncology (2023)

The Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) with untreated brain metastases, a population traditionally excluded from trials.This single-arm phase II clinical trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years. The primary end points were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria.Forty patients were enrolled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2 but five patients (12.5%) experienced grade 3-4 neurologic events. With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS) was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI, 16.6 to 45.5).Atezolizumab plus carboplatin and pemetrexed demonstrates activity in patients with advanced nonsquamous NSCLC with untreated brain metastases with an acceptable safety profile.
Improved Posttransplant Outcomes in Recent Years for AML Patients with <i>FLT3</i>-ITD and Wild-type <i>NPM1</i>: A Report from the EBMT Acute Leukemia Working Party
Authors: Ali Bazarbachi, Myriam Labopin, Tobias Gedde-Dahl, Peter Remenyi, Edouard Forcade, Nicolaus Kröger, Gerard Socié, Charles Craddock, Jean Henri Bourhis, Jurjen Versluis, Ibrahim Yakoub-Agha, Urpu Salmenniemi, Jean El-Cheikh, Gesine Bug, Jordi Esteve, Arnon Nagler, Fabio Ciceri, Mohamad Mohty
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1) in patients with acute myeloid leukemia (AML) harboring FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD). We assessed changes over time in transplant characteristics and outcomes in patients with AML age 60 years and younger with a FLT3-ITD. Experimental Design: We identified 1,827 adult patients with AML (median age 49 years, range 18–60) with FLT3-ITD and intermediate karyotype, allografted between 2012 and 2021 in CR1. Results: NPM1 was mutated in 72% of patients. We compared changes over time in 688 patients transplanted between 2012 and 2016, and 1,139 patients transplanted between 2017 and 2021. For patients with wild-type NPM1, the 2-year leukemia-free survival (LFS) and overall survival (OS) significantly improved over time from 54% to 64% (HR = 0.67; P = 0.011) and from 63% to 71% (HR = 0.66; P = 0.021), respectively. Allo-HCT in recent years significantly reduced the cumulative incidence of relapse (CIR). For patients with NPM1 mutation, no significant changes over time were noted. Conclusions: In patients with AML with FLT3-ITD and wild-type NPM1, we noticed a significant decrease over time in the CIR and improvement of LFS and OS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as posttransplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in outcomes of patients harboring a FLT3 and NPM1 mutation.
Bicuspid Aortic Valve and Thoracic Aortic Disease: Further Evidence of Clinically Silent but Deadly Risk to Family Members of Affected Individuals
Authors: Siddharth K. Prakash, Hector I. Michelena, Dianna M. Milewicz
Journal: Circulation (2023)

icuspid aortic valve (BAV) and thoracic aortic aneurysms (TAAs) leading to aortic dissections, called thoracic aortic disease (TAD), are highly heritable and cause a significant cumulative burden of lifetime morbidity.The most frequent complications of BAV are aortic valve stenosis, which requires surgical valve repair in more than half of patients, and the development of TAD in at least 25% of patients. 1In up to 20% of cases, BAV, TAD, or both conditions are transmitted in families as primarily autosomal dominant traits with variable penetrance and expressivity. 2In fact, family-based estimates place the heritability of BAV as high as 0.9. 3 Characteristically, probands with more severe clinical phenotypes (ie, young at presentation, dissections or symptomatic disease, additional congenital cardiovascular lesions) are more likely to have affected relatives. 4In families with TAD with multiple affected relatives, called heritable TAD, the causative gene is identified in only 30% of cases, and the percentage of families with BAV with solved genes is even lower.Despite similar phenotypes, current data suggest that the overlap of causative genes for BAV and heritable TAD is minimal.